Hypothesis: Adaptation of the brain's functional responses to the time course of exposure to alcohol is associated with a differential familial risk for alcoholism. The long term goals of this project are to identify the human brain's adaptive responses to alcohol that signify an increased risk for becoming alcohol dependent, so that assays of increased individual risk can be established, and so that a platform for developing pharmaceuticals targeted at acute adaptation to alcohol can be constructed. In the current grant cycle, a method for clamping breath alcohol concentration (BrAC) at a steady state was used to document both initial and adaptive responses to alcohol that distinguish subjects with a differential family history for alcoholism. In Specific Aim 1, the multi-disciplinary study of acute tolerance will be extended to include new methods, refined dependent measures and a two-session experimental design all intended to provide increased sensitivity to the association of FHA with differences in the brain's adaptive responses to alcohol. The influence of secondary risk factors for alcoholism (age of onset of drinking, alcohol elimination rate, and a composite measure of baseline central nervous system disinhibition) will also be explored. In Specific Aim 2, advanced BrAC clamping techniques will be used to systematically vary the slopes of the ascending and descending phases of the brain's exposure to alcohol, and the best 2-session paradigm for quantifying the effect of rate of change of BrAC on 3 continuous measures of brain function will be chosen. In Specific Aim 3, the result will be used to test for the influence of a family history for alcoholism land recent: drinking history on the relationship between the rate of change of alcohol exposure and brain function.